Aurora Kinase Inhibitors - Rising Stars in Cancer Therapeutics?

Abstract

Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy.Mol Cancer Ther; 9(2); 268-78. ©2010 AACR.

ENMD-2076 Is an Orally Active Kinase Inhibitor with Antiangiogenic and Antiproliferative Mechanisms of Action

“…We show here that ENMD-2076 inhibits a unique profile of tyrosine kinase targets, in addition to Aurora A which is a key regulator of the process of mitosis and is often overexpressed in human cancers (7,8). ENMD-2076 is shown to have substantial impact on several of the most important pathways involved in mitosis and angiogenesis and inhibition of these processes is likely to contribute to the substantial antitumor activity of the compound as a single agent at welltolerated doses in a variety of preclinical tumor models.…”

“…ENMD-2076 is the tartrate salt of a novel vinyl pyrimidine chemical entity that originated from an effort to develop inhibitors of the Aurora kinases, which have received considerable attention as potential oncology drug targets in recent years (7,8,30). The vinyl pyrimidine core of ENMD-2076 is unique amongst Aurora kinase inhibitors; although, it is a property of the structures of other compounds inhibiting targets such as Tie-2 (31), Src and Abl (32), phosphatidylinositol 3-kinase and mTOR (33).…”

Response to MLN8237 in Pancreatic Cancer Is Not Dependent on RalA Phosphorylation

“…However, we were unable to correlate this with RalA S194 phosphorylation levels. AAK activity is temporally controlled with peak activity during mitosis (42). It is possible that Aurora A phosphorylation of RalA at S194 is strictly temporally controlled, making it difficult to observe consistent changes following MLN8237 treatment in an asynchronous cell population.…”

Insilico Discovery of Human Aurora B Kinase Inhibitors by Molecular Docking, Pharmacophore Validation and Admet Studies

“…Aurora's are a family of well homologous serine-threonine protein kinases that play an important role in controlling a series of activities at different stages from G2 to cytokinesis during cell division through which normal cell cycle mitosis is maintained [4][5][6]. The mitotic regulation is necessary for equal and accurate chromosomal segregation to daughter cells during cell division and is of great consequence to preserve genome stability and prevent aneuploidy [7][8][9].…”